Facilitating meniscus healing through SDF-1/CXCR4 axis modified cell-therapy

通过 SDF-1/CXCR4 轴修饰细胞疗法促进半月板愈合

• 批准号: 10132243
• 负责人: Chathuraka Teekshana Jayasuriya
• 金额: $ 17.18万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132243
• 关键词: Adipocytes; Adipose tissue; Animal Model; Arthritis; Behavior; Biological; Biological Response Modifier Therapy; Biomechanics; Bone Marrow; CXCR4 Receptors; CXCR4 gene; Cartilage; Cell Therapy; Cells; Clinical; Data; Degenerative polyarthritis; Development; Engraftment; Fibrocartilages; Future; Gene Delivery; Gene-Modified; Goals; Histology; Human; Hypertrophy; In Vitro; Injury; Investigation; Joints; Knee; Knowledge; Literature; Measures; Mechanics; Medial meniscus structure; Mediating; Meniscus structure of joint; Mesenchymal; Mesenchymal Stem Cells; Mission; Modeling; Musculoskeletal; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural regeneration; Nature; Organism; Oryctolagus cuniculus; Patients; Pilot Projects; Public Health; Publishing; Reporting; Research; Research Design; Risk Factors; Rodent Model; Site; Solid; Stromal Cell-Derived Factor 1; Synovial Membrane; Testing; Tissues; United States National Institutes of Health; articular cartilage; base; chemokine receptor; disability; efficacy evaluation; healing; human DNA; improved; in vivo; injury and repair; innovation; joint injury; mechanical force; meniscal tear; meniscus injury; musculoskeletal injury; overtreatment; prevent; repair strategy; repaired; response; response to injury; scale up; stem; stem cells; tissue regeneration; tissue repair; trafficking; Adipocytes; Adipose tissue; Animal Model; Arthritis; Behavior; Biological; Biological Response Modifier Therapy; Biomechanics; Bone Marrow; CXCR4 Receptors; CXCR4 gene; Cartilage; Cell Therapy; Cells; Clinical; Data; Degenerative polyarthritis; Development; Engraftment; Fibrocartilages; Future; Gene Delivery; Gene-Modified; Goals; Histology; Human; Hypertrophy; In Vitro; Injury; Investigation; Joints; Knee; Knowledge; Literature; Measures; Mechanics; Medial meniscus structure; Mediating; Meniscus structure of joint; Mesenchymal; Mesenchymal Stem Cells; Mission; Modeling; Musculoskeletal; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural regeneration; Nature; Organism; Oryctolagus cuniculus; Patients; Pilot Projects; Public Health; Publishing; Reporting; Research; Research Design; Risk Factors; Rodent Model; Site; Solid; Stromal Cell-Derived Factor 1; Synovial Membrane; Testing; Tissues; United States National Institutes of Health; articular cartilage; base; chemokine receptor; disability; efficacy evaluation; healing; human DNA; improved; in vivo; injury and repair; innovation; joint injury; mechanical force; meniscal tear; meniscus injury; musculoskeletal injury; overtreatment; prevent; repair strategy; repaired; response; response to injury; scale up; stem; stem cells; tissue regeneration; tissue repair; trafficking

PROJECT SUMMARY/ABSTRACT Fibrocartilage tears in the avascular white-white zone of the meniscus are a significant clinical challenges due to their inability to heal. These common injuries are independent risk factors for the development of post-traumatic osteoarthritis. The long-term goal is to develop innovative cellular biologic therapies geared to stimulate healing of white-white zone meniscus tears in patients. Preliminary studies demonstrate that cartilage-derived mesenchymal progenitors (CPCs) can be used as a cell-therapy to effectively repair meniscus tears in a rodent model. However, since the long-term goal involves effectively treating human patients, there exists a knowledge gap as to how the beneficial healing effect of CPCs can be scaled up to in order to effectively repair menisci in larger animal models. The objective of this project to evaluate the efficacy of CXCR4 gene modified CPC therapy as a means of facilitating white-white zone tissue healing in a rabbit meniscus injury model. The central hypothesis is that treating white- white zone meniscus tears with CPCs that have elevated chemokine receptor CXCR4 will increase their cell localization to the site of injury and improve the extent and quality of the resulting healing response. This central hypothesis will be tested by completing two specific aims: (1) Measure the extent cell engraftment that results from gene delivery of CXCR4 into CPCs; (2) Evaluate the efficacy of meniscus repair resulting from CXCR4 gene modified cell therapy. The research design is to employ a gene delivery approach to modify the expression of the chemokine receptor CXCR4, which is a regulator cell trafficking in response to injury, in order to increase cell localization and engraftment to white-white zone meniscus injury sites. It is expected that this will improve meniscus injury repair as measured by biomechanical tensile testing and histology. Successful completion will have a positive impact by laying the groundwork for developing an effective new strategy to stimulate meniscus injury repair through the use of cellular biologics. This project is relevant to the mission of NIAMS because it seeks to find innovative ways to treat musculoskeletal injuries and prevent arthritis.

项目摘要/摘要 半月板的血管白白白色区域中的纤维球撕裂是一个重要的临床 挑战由于无法治愈。这些常见伤害是独立的风险因素 创伤后骨关节炎的发展。长期目标是发展创新 细胞生物学疗法旨在刺激白色区域弯月板撕裂的愈合 患者。初步研究表明，软骨衍生的间充质祖细胞 （CPC）可以用作细胞疗法，以有效修复啮齿动物模型中的弯月板撕裂。 但是，由于长期目标涉及有效治疗人类患者，因此存在 关于如何将CPC的有益治疗效应缩放到以便为了缩放的知识差距 有效修复大型动物模型中的半月板。该项目的目的是评估 CXCR4基因修饰的CPC疗法的功效作为促进白人区域的一种手段 在兔半月板损伤模型中的组织愈合。中心假设是处理白色 白色区域半月板撕裂具有趋化因子受体CXCR4升高的CPC 将其细胞定位到受伤部位，并提高 产生的愈合反应。该中心假设将通过完成两个特定的测试 目的：（1）测量CXCR4基因递送基因导致的细胞植入范围 CPCS; （2）评估CXCR4基因修饰细胞产生的半月板修复的功效 治疗。研究设计是采用基因输送方法来修改表达 趋化因子受体CXCR4（是响应损伤的调节剂细胞运输）中的 为了增加细胞定位并植入到白色白色区域弯月板损伤部位。这是 预计这将改善通过生物力学拉伸测量的半月板损伤修复 测试和组织学。成功完成将通过建立积极影响 制定有效的新策略以刺激弯月板损伤维修的基础 使用细胞生物制剂。该项目与Niams的使命有关，因为它寻求 寻找创新的方法来治疗肌肉骨骼损伤并预防关节炎。